We have documented that infection of rhesus macaques (Macaca mulatta) with Simian Immunodeficiency Virus (SIV/Delta), a virus morphologically, antigenically, and genetically related to HIV, induces an immunodeficiency disease (SAIDS) which parallels human AIDS. As a result of these studies, we have cryopreserved multiple isolates of SIV of known pathogenic potential for further study. Of particular interest are related isolates which are neurovirulent (SIV/DeltaB670), pathogenic non-neurovirulent (SIV/DELTA8664), and non-pathogenic (SIV/DeltaD915). We propose to identify regions of the viral genome responsible for both neurovirulence and pathogenicity and determine the function of these sequences in vivo and in vitro. Rhesus monkeys inoculated with SIV/DeltaB670 will be evaluated immunologically to determine immune alterations unique to neurovirulence. Viral replication and expression in the monocyte will be compared in primary monocytes infected with neurovirulent, pathogenic non- neurotropic, and nonpathogenic isolates. SIV/DeltaB670 and its parental isolate, which is pathogenic but non-neurotropic, will be molecularly cloned and sequenced along with a related lab- attenuated isolate. Infectious cloned virus of pathogenic isolates will be examined in vivo for retention of pathogenicity. A comparison of the nucleotide sequences of these 3 isolates, by identifying regions of divergence, will define genetic domains of potential functional relevance to pathogenesis. Thereafter, genome recombinants of neurovirulent, pathogenic, and non- virulent isolates will be constructed and assayed for pathogenicity in vivo to identify viral genes responsible. With the invaluable resource of the susceptible primate host, the rhesus monkey, these proposed experiments will both characterize in detail pathogenic isolates of SIV and relate their molecular structure to both pathogenesis and neurovirulence. Furthermore, the availability of a completely characterized neurovirulent isolate of SIV will permit further studies of virus-induced neuropathy in the host and evaluation of measures for effective disease prevention.